The present invention provides an improved process for the preparation of imidazolidinone xcex1vxcex23/xcex1vxcex25 integrin antagonists of general structural formula (I). 
The present invention also provides intermediates useful in the disclosed process.
The compounds of structural formula (I), along with their use as xcex1vxcex23/xcex1vxcex25 integrin antagonists for inhibiting bone resorption and treating and/or preventing osteoporosis, were disclosed in U.S. Pat. No. 6,017,926 (Jan. 25, 2000), which is incorporated by reference herein in its entirety, and in WO 99/31099 (published Jun. 24, 1999). The compounds disclosed therein are also useful in inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammatory arthritis, cancer, and metastatic tumor growth.
U.S. Pat. No. 6,017,926 also described a process for preparing the compounds of formula (I). However, a large number of synthetic transformations was required (the longest linear sequence being about 14 steps) with an overall yield of less than 5%. Silica gel column chromatography was required after most of the steps, and final products were obtained with an enantiomeric purity of less than 90%.
With the present invention there are produced more efficiently compounds of structural formula (I) with an enantiomeric purity in excess of 99% in considerably fewer chemical steps (the longest linear sequence being 10 steps) with an overall yield of about 30%. Moreover, a smaller number of chromatographic purification steps is necessary throughout the synthetic sequence.
This invention is concerned with a process for preparing compounds of structural formula (I) and certain useful intermediates obtained during that process. 
The novel process and novel intermediates can be exemplified in the following embodiment, which illustrates the preparation of 3-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]imidazolidin-1-yl}-3(S)-(6-methoxypyridin-3-yl)-propionic acid (3-4). The overall process converges two Series A and B of reaction steps, each producing a key intermediate, into a third Series C of steps in which the two intermediates are combined to ultimately produce the desired products of structural formula (I). Series A affords intermediates exemplified by 2-6, and Series B yields intermediates exemplified by 1-8. 
Also provided are intermediate compounds which are useful for the preparation of compounds of structural formula (I).
Another aspect of the present invention provides compound 3-4 in the form of a hemihydrate as well as a method for the preparation of the hemihydrate.
The products of the present process are antagonists of xcex1vxcex23/xcex1vxcex25 integrin receptors and therefore useful for inhibiting bone resorption and treating and/or preventing osteoporosis. They are also useful in inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammnatory arthritis, cancer, and metastatic tumor growth.
The present invention provides an efficient process for the preparation of compounds of structural formula (I): 
wherein
Ar is mono- or di-substituted phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazolyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, indolyl, isoindolyl, purinyl, or carbazolyl, wherein the substituent is independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, C3-6 cycloalkyl, C1-3 acylamino, C1-4 alkoxy, C1-5 alkoxycarbonyl, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C1-4 alkylamino, di-C1-4 alkylamino, and C1-5 alkylcarbonyloxy; and
R1 is selected from the group consisting of hydrogen, halogen, C1-10 alkyl, C3-6 cycloalkyl, and C1-3 alkoxy;
which comprises the steps of:
(a) producing a compound of structural formula (III): 
xe2x80x83wherein R2 is C1-4 alkyl and R3 is C1-4 alkyl, phenyl-C1-3 alkyl, diphenylmethyl, or triphenylmethyl;
xe2x80x83by treating a compound of structural formula (V): 
with glyoxal-1,1-di-C1-4 alkyl acetal in the presence of a reducing agent and isolating the resulting product;
(b) preparing a compound of structural formula (II): 
xe2x80x83by treating an amine of structural formula (III): 
wherein R2 is C1-4 alkyl and R3 is C1-4 alkyl, phenyl-C1-3 alkyl, diphenylmethyl, or triphenylmethyl;
xe2x80x83with an amine of structural formula (IV), 
wherein R1 is as defined above, in the presence of phosgene or a phosgene equivalent and base to produce a compound of structural formula (VI): 
xe2x80x83followed by treatment with aqueous acid;
(c) cleaving the R3 protecting group in a compound of structural formula (II) to afford a compound of structural formula (VII), 
(d) reducing the imidazolin-2-one double bond in a compound of structural formula (VII), and
(e) isolating the resulting product.
The order in which the last two steps of the process of the present invention are carried out may be reversed such that the imidazolin-2-one double bond in a compound of structural formula (II): 
is first reduced to afford a compound of structural formula (VIII): 
and the R3 protecting group in a compound of structural formula (VIII) is then cleaved to afford a compound of structural formula (I).
In one embodiment of the present invention, there is provided a process for preparing a compound of structural formula (I): 
wherein
Ar is mono-or di-substituted phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazolyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, indolyl, isoindolyl, purinyl, or carbazolyl, wherein the substituent is independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, C3-6 cycloalkyl, C1-3 acylamino, C1-4 alkoxy, C1-5 alkoxycarbonyl, cyano, trifluoromethyl, hydroxy, trifluoromethoxy, amino, C1-4 alkylamino, di-C1-4 alkylamnino, and C1-5 alkylcarbonyloxy; and
R1 is selected from the group consisting of hydrogen, halogen, C1-10 alkyl, C3-6 cycloalkyl, and C1-3 alkoxy;
which comprises the steps of:
(a) cleaving the R3 protecting group in a compound of structural formula (II): 
xe2x80x83wherein R3 is C1-4 alkyl, phenyl-C1-3 alkyl, diphenylmethyl, or triphenylmethyl, to afford a compound of structural formula (VII);
(b) reducing the imidazolin-2-one double bond in a compound of structural formula (VII); and
(c) isolating the resulting product.
In another embodiment of the present invention, the imidazolin-2-one double bond in a compound of structural formula (II) is first reduced to afford a compound of structural formula (VIII) followed by cleavage of the R3 protecting group to afford a compound of structural formula (I).
In a class of these two embodiments, R3 is tert-butyl.
In a second class class of these two embodiments, R1 is hydrogen and Ar is 6-methoxy-pyridin-3-yl. In a subclass of this class of these two embodiments, Ar is (S)-6-methoxy-pyridin-3-yl.
In a third class of these two embodiments, the imidazolin-2-one double bond is reduced by catalytic hydrogenation.
In a third embodiment of the present invention, there is provided a process for preparing a compound of structural formula (II): 
which comprises treating an amine of structural formula (III): 
wherein R2 is C1-4 alkyl and R3 is C1-4 alkyl, phenyl-C1-3 alkyl, diphenylmethyl, or triphenylmethyl;
with an amine of structural formula (IV): 
wherein R1 is as defined above, in the presence of phosgene or a phosgene equivalent and base to produce a compound of structural formula (VI): 
xe2x80x83followed by treatment with aqueous acid, and isolating the resulting product.
In a class of this embodiment, the phosgene equivalent is chlorocarbonic acid trichloromethyl ester or bis(trichloromethyl) carbonate (triphosgene). In a subclass of this class, the phosgene equivalent is bis(trichloromethyl) carbonate (triphosgene).
In another class of this embodiment, the base is an organic base, such as triethylamine, and the aqueous acid is aqueous sulfuric acid.
The preparation of compounds of structural formula (IV) is disclosed herein as well as in U.S. Pat. Nos. 5,952,341 and 6,048,861, WO 98/18460, and WO 99/31061.
In a fourth embodiment of the present invention, there is provided a process for producing a compound of structural formula (III): 
by treating a compound of structural formula (V): 
with glyoxal-1,1-di-C1-4 alkyl acetal in the presence of a reducing agent, and isolating the resulting product.
In a class of this embodiment, glyoxal-1,1-di-C1-4 alkyl acetal is glyoxal-1,1-dimethyl acetal.
In a second class of this embodiment, the reducing agent is sodium cyanoborohydride or sodium triacetoxyborohydride.
Further embodiments of this invention comprise the following novel compounds which are intermediates in the preparation of 3-4 and other compounds of structural formula (I): 
In a class of this embodiment is the p-toluenesulfonate salt of 3(S)-(6-methoxy-pyridin-3-yl)-xcex2-alanine tert-butyl ester.
The novel process and novel intermediates can be exemplified with the preparation of 3-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]imidazolidin-1-yl}-3(S)-(6-methoxy-pyridin-3-yl)-propionic acid (3-4). The overall process of this invention comprises three parts. Each of parts 1 and 2, illustrated by Schemes 1 and 2, provides a key intermediate and part 3 illustrated by Scheme 3, joins these two key intermediates, ultimately leading to the desired compounds 3-3 and 3-4. 
The known 2-amino-3-formyl-pyridine 1-3 is prepared as shown in Scheme 1 above. Compound 1-4 is prepared by a Friedlander reaction which comprises treatment of 1-3 in a solvent such an aqueous alcohol, for example aqueous methanol or ethanol, and pyruvic aldehyde dimethyl acetal at a temperature range of about 0xc2x0 C. to about 55xc2x0 C. with aqueous alkali such as 3-7 M sodium or potassium hydroxide. An alkali metal alkoxide, such as sodium, potassium, or lithium methoxide or ethoxide, or an organic base, such as piperidine or proline, may also employed as the base in the reaction. After aging for about 0.5 to about 2 hours, the product 1-4 is isolated.
Compound 1-5 is prepared by hydrogenating 1-4 in a solvent, such as a lower alkanol, for example, methanol or ethanol, in the presence of a noble metal catalyst such as PtO2 at or about atmospheric pressure until hydrogen uptake ceases. Other catalysts which can be employed in the hydrogenation reaction include Raney nickel, Pd/C, Rh/C, Ru/C, Pd/Al2O3, Pt/C, Pt/Al2O3, Rh/Al2O3, and Ru/Al2O3.
Compound 1-5 is treated with aqueous HCl, and the mixture is heated from about 75xc2x0 C. to about 95xc2x0 C. for about 1-4 hours. Other acids which can be used in the hydrolysis reaction include sulfuric acid, trifluoroacetic acid, and methanesulfonic acid. After cooling, isopropyl acetate (iPAc) is added, and the mixture is made slightly alkaline with aqueous alkali, and the product 1-6 is isolated by liquid/liquid extraction.
The preparation of compounds 1-4, 1-5, and 1-6 has also been described in U.S. Pat. No. 5,981,546 and WO 98/08840 (published March 5, 1998) using variants of the above conditions.
Compound 1-7 is prepared via a Wittig reaction, such as the Homer-Emmons modification, by treatment of a solution of compound 1-6 and diethyl (cyanomethyl)phosphonate in a suitable solvent, such as THF and toluene, with a strong alkali metal hydroxide, such as sodium hydroxide, followed by continued stirring for about 0.5-2 hours. Other bases, such an alkyl lithium, sodium methoxide, potassium tert-butoxide, lithium diisopropylarnide, lithium or sodium hexamethyldisilazide, or alkylmagnesium halide, may also be used in place of the alkali metal hydroxide. The reaction can be carried out at a temperature range of about xe2x88x9280xc2x0 C. to 110xc2x0 C. The product 1-7 is isolated by dilution with iPAc and separation of the organic layer.
The key intermediate 1-8 is prepared by treating a suspension of 1-7 in saturated aqueous ammonium hydroxide with hydrogen gas under medium to high pressure in the presence of a Raney nickel 2800 catalyst. For each mole of nitrile 1-7, there is employed about 1.5 to about 3 moles of ammonium hydroxide solution. Other catalysts which can be used in the reduction include Pd/C, Pd(OH)2/C, Pd/Al2O3, Pt/C, Pt/Al2O3, PtO2, Rh/Al2O3, and Raney nickel 3111, 5601, 2700, and 2724.
Intermediate 1-8 can also be prepared following the procedures disclosed in U.S. Pat. No. 6,048,861, which is incorporated by reference herein in its entirety. 
As shown in Scheme 2 above, compound 2-1 is brominated by treatment with bromine in an organic solvent such as methylene chloride, chloroform, 1,2-dichloroethane, or the like, in the presence of sodium acetate at a temperature below about 10xc2x0 C. to yield compound 2-2.
Compound 2-2 is converted to compound 2-3 in a Heck-type procedure by adding it to a mixture comprised of an alkyl acrylate, such as methyl, ethyl, or t-butyl acrylate, in the presence of a strong organic base such as triethylamine, in a solvent such as N,N-dimethylformamide (DMF) or N-methylpyrrolidinone (NMP), a phosphine ligand such as triphenylphosphine or tri-o-tolylphosphine, and a palladium catalyst such as palladium acetate, and heating the mixture at about 80xc2x0 C. to about 125xc2x0 C. In one embodiment of the Heck reaction, the temperature is maintained at 90-95xc2x0 C. Oxidation of the phosphine with a solution of sodium hypochlorite (NaOCl) to the phosphine oxide allows for simple removal of the phosphine oxide from the Heck reaction mixture by filtering through a pad of silica gel.
Compound 2-4 is formed by a chiral Michael addition of the lithium amide derived from N-benzyl-(R)-2-methylbenzylamine and n-butyllithium to compound 2-2 in an organic solvent, such as tetrahydrofuran, at about xe2x88x9270xc2x0 C. to xe2x88x9240xc2x0 C. These conditions have been described by Davies et al. in Tetrahedron: Asymmetry, Vol.2, pp.183-186, 1991. Other bases, such as n-hexyl lithium, may also be used in place of n-butyl lithium. Use of N-benzyl-(S)-2-methylbenzylamine in place of N-benzyl-(R)-2-methylbenzylamine affords the 3(R)-diastereoisomer of 2-4.
Compound 2-5 is obtained by reduction of compound 2-4 with H2 at about 40 psi and 20% Pd(OH)2 in ethanol and acetic acid. After removal of the catalyst and evaporation of the ethanol, the resulting amine is then treated with a solution of para-toluenesulfonic acid in an ethereal solvent, such as methyl t-butyl ether (MTBE), to form the para-toluenesulfonate (p-TSA) salt 2-5. The p-TSA salt was found to be highly crystalline, and crystallization of this salt was found to enhance the enantiomeric purity of 2-5.
The key intermediate 2-6 and the process for its synthesis form separate embodiments of this invention. The process comprises a two-carbon homologation by reductive alkylation of the amine 2-5 with glyoxal-1,1-di-C1-4 alkyl acetal, under the influence of a complex metal hydride in water, an organic solvent, or aqueous organic solvent, such as aqueous THF or aqueous methanol. The complex metal hydride, such as NaBH3CN, Na(OAc)3BH, sodium borohydride, or tetrabutylammonium borohydride, is either added as a solid portionwise or taken up in an organic solvent such as methanol, ethanol, acetic acid, tetrahydrofuran, or dichloromethane and added to the reaction mixture. 
In reaction Scheme 3, a mixture of the acetal 2-6 and triethylamine in anhydrous THF is slowly added to a cold (xe2x88x9215xc2x0 C. to 15xc2x0 C.) solution of bis(trichloromethyl)carbonate (triphosgene) in anhydrous THF while keeping the temperature below about 0xc2x0 C. to about 10xc2x0 C. Phosgene or another phosgene equivalent, such as chlorocarbonic acid trichloromethyl ester, may also be used in place of triphosgene. After aging, the reaction mixture is kept at that temperature for about 15 to 45 minutes and then at about room temperature for another 15 to 45 minutes, the excess triphosgene is purged and the amine 1-8 and a base, such as triethylamine, are added at about 0xc2x0 C. to about 10xc2x0 C. and the suspension is stirred at about 30xc2x0 C. to 50xc2x0 C. for about 5 to 7 hours. Compound 3-1, produced by the above process, is used directly in the synthesis of compound 3-2. The reaction mixture is cooled to room temperature, aqueous acid, such as aqueous sulfuric acid or aqueous hydrochloric acid, is added, the mixture is stirred for about 8 to 12 hours and then added to a mixture of iPAc and aqueous sulfuric acid or hydrochloric acid and the product 3-2 is isolated by solvent/solvent extraction after adjusting the pH.
The t-butyl ester group of 3-2 is cleaved to yield 3-3 by treatment with an acid such as trifluoroacetic acid, formic acid, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, or the like, at a temperature from about room temperature to about 50xc2x0 C. until the reaction is complete, usually about 3 to 6 hours. Compound 3-3 was found to be highly crystalline, which allowed for enhancement of the enantiomeric and chemical purity of the final product 3-4 at the penultimate stage of the reaction sequence. Crystalline 3-3 obtained from solutions containing water and acetone exhibited three distinct X-ray powder diffraction patterns (I, II, and III) depending upon the water content in the crystals: Pattern I (with characteristic diffraction peaks corresponding to d-spacings of 3.4, 3.5, 4.9, 5.3, 6.2 and 8.1 angstroms) was observed for crystals with water content in the range of 5 to 9%; Pattern II (with characteristic diffraction peaks corresponding to d-spacings of 3.5, 3.6, 4.8, 5.5, 6.0, and 8.3 angstroms) was observed for crystals with water content in the range of 13 to 16%; and Pattern III (with characteristic diffraction peaks corresponding to d-spacings of 3.4, 3.5, 3.6, 3.8, 4.1, 5.0 and 15.7 angstroms) was observed for crystals with water content in the range of 33 to 41%. Crystalline 3-3 obtained from solutions containing water and isopropanol exhibited patterns having characteristic diffraction peaks corresponding to d-spacings of 3.5, 3.8-3.9, 4.4, 4.5-4.6, 6.4 and 18.9-19.0 angstroms. In addition, each of these patterns contained a peak corresponding to a d-spacing in the vicinity of 12.6 to 15.7 angstroms, depending on the water content of the crystal. Crystals containing 2.3% water showed a peak at 12.6 angstroms (pattern IV); crystals containing about 3.3% water displayed a peak at 13.0 angstroms (pattern V); and crystals containing higher levels of residual solvent showed a peak at 15.7 angstroms (pattern VI).
Compound 3-4 is produced by reducing the double bond in 3-3, such as by hydrogenation in a solvent such as water, aqueous methanol, or aqueous ethanol, with hydrogen at medium pressure in the presence of an alkali metal hydroxide, such as sodium or potassium hydroxide, or an amine base, such as ammonia or an alkylamine, for example, triethylamine, in the presence of a noble catalyst such as palladium hydroxide on carbon, palladium black, or palladium-on-charcoal.
When crystallized from water, filtered, and dried at room temperature under nitrogen for up to about 24 hours, compound 3-4 is obtained in the form of a hemihydrate as evidenced by Karl-Fischer titration and thermogravimetric analysis (TGA). The crystalline hemihydrate is characterized by the positions and intensities of the major peaks in the X-ray powder diffraction pattern as well as its FT-IR spectrum.
Compound 3-4 may also be prepared as shown in the Scheme below by first reducing the double bond in 3-2 under the conditions described above to afford saturated t-butyl ester 3-5 and then cleaving the t-butyl ester group in 3-5 to give 3-4 under the conditions described above. 
Representative experimental procedures utilizing the novel process are detailed below. For purposes of illustration, the following Example is directed to the preparation of compounds 3-3 and 3-4, but doing so is not intended to limit the present invention to a process for making those specific compounds.
Abbreviations: AcOH is acetic acid; BuLi is n-butyl lithium, CH2Cl2 is dichloromethane; EtOAc is ethyl acetate; Et3N is triethylamine; iPAc is isopropyl acetate; MTBE is methyl t-butyl ether; NMP is N-methylpyrrolidinone; NaOCl is sodium hypochlorite; NMR is nuclear magnetic resonance; Na2CO3 is sodium carbonate; NaHCO3 is sodium hydrogencarbonate; NaCNBH3 is sodium cyanoborohydride; NaBH(OAc)3 is sodium triacetoxyborohydride; PtO2 is platinum oxide; P(otol)3 is tri-o-tolyl-phosphine; p-TsOH is para-toluenesulfonic acid; and THF is tetrahydrofuran.
By halogen is meant fluorine, chlorine, bromine, or iodine.
The FT-IR spectrum of 3-4 was obtained on a Nicolet 510P Fourier-Transform infrared spectrometer.
The differential scanning calorimeter (DSC) curve was taken on a TA 2910 Differential Scanning Calorimeter with a heating rate of 10xc2x0 C./minute under nitrogen.
X-ray powder diffraction patterns were generated on a Philip Analytical X-ray diffractometer using Cu Kxcex1 radiation.